Transdermal compositions comprising an active agent layer and an active agent conversion layer

ABSTRACT

Transdermal compositions are provided. Aspects of the transdermal compositions include: an active agent layer and a conversion layer, where the conversion layer includes a weak base and, optionally, a carboxylated component. Also provided are methods of using the transdermal compositions and kits containing the transdermal compositions.

CROSS-REFERENCE TO RELATED APPLICATIONS

Pursuant to 35 U.S.C. §119 (e), this application claims priority to thefiling dates of: U.S. Provisional Patent Application Ser. No. 61/467,337filed on Mar. 24, 2011; the disclosure of which application is hereinincorporated by reference.

INTRODUCTION

There is a constant need to administrate physiologically active agents,such as anti-Parkinson agents, into human body. Oral administration isthe most commonly used method because it is relatively simple to do.However, the oral administration route is often complicated withgastrointestinal irritation and drug metabolism in the liver.

Administration through human skin (transdermal drug delivery) is analternative route to oral administration and can provide some advantagessuch as the avoidance of first pass metabolism, controlled delivery,more simple dosing regime, and better patient compliance. Transdermalactive agent compositions, also known as transdermal patches or skinpatches, are adhesive patches containing an active agent that are placedon the skin to deliver the active agent through the skin. Transdermalpatches deliver the active agent by percutaneous absorption, which isthe absorption of substances through unbroken skin. After a transdermalpatch is applied to the skin, the active agent contained in the patchpasses through, or permeates the skin and can reach its site of actionthrough a systemic blood flow. Alternatively, the transdermal patch maybe placed on the desired treatment site such that the medicationcontained in the patch is delivered topically.

One major drawback of transdermal route is the limitation of the amountof drug that can be transported across the skin. In order to increasethe amount of drug going through skin, drug molecules in free base formare typically used in transdermal route. Drug in free base form isusually not as stable as drug in salt form. Therefore, stability of drugin transdermal formulations often causes concern. Another approach toincrease skin permeation is to use chemical enhancers in theformulation. While delivery through skin can often be increased with theuse of enhancers, they often induce more skin irritation.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A and 1B show cross sectional views of two different embodimentsof the transdermal active agent formulation in accordance with theinvention.

FIGS. 2 to 6 show graphs of flux as a function of time (middle pointbetween the two sampling time points) for various formulations.

SUMMARY OF INVENTION

Transdermal compositions are provided. Aspects of the transdermalcompositions include: an active agent layer and a conversion layer,where the conversion layer includes a weak base and, optionally, acarboxylated component. Also provided are methods of using thetransdermal compositions and kits containing the transdermalcompositions.

DETAILED DESCRIPTION

Transdermal compositions are provided. Aspects of the transdermalcompositions include: an active agent layer and a conversion layer,where the conversion layer includes a weak base and, optionally, acarboxylated component. Also provided are methods of using thetransdermal compositions and kits containing the transdermalcompositions.

Before the present invention is described in greater detail, it is to beunderstood that this invention is not limited to particular embodimentsdescribed, as such may, of course, vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present invention will be limited only by the appendedclaims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges and are also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the invention.

Certain ranges are presented herein with numerical values being precededby the term “about.” The term “about” is used herein to provide literalsupport for the exact number that it precedes, as well as a number thatis near to or approximately the number that the term precedes. Indetermining whether a number is near to or approximately a specificallyrecited number, the near or approximating unrecited number may be anumber which, in the context in which it is presented, provides thesubstantial equivalent of the specifically recited number.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, representativeillustrative methods and materials are now described.

All publications and patents cited in this specification are hereinincorporated by reference as if each individual publication or patentwere specifically and individually indicated to be incorporated byreference and are incorporated herein by reference to disclose anddescribe the methods and/or materials in connection with which thepublications are cited. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention. Further, the dates ofpublication provided may be different from the actual publication dateswhich may need to be independently confirmed.

It is noted that, as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimsmay be drafted to exclude any optional element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentinvention. Any recited method can be carried out in the order of eventsrecited or in any other order which is logically possible.

In further describing various embodiments of the invention, aspects ofthe transdermal compositions are reviewed first in greater detail,followed by a detailed description of embodiments of using thetransdermal delivery systems and a review of kits that include thetransdermal delivery systems.

Transdermal Compositions

As summarized above, transdermal compositions are provided. Transdermalcompositions of the invention are formulations that are configured totransdermally deliver an active agent to a subject when topicallyapplied to a skin surface of a subject. The compositions of theinvention include two or more layers, where the two or more layersinclude at least an active agent layer and a conversion layer, whereinthe two or more layers are configured to provide for multi-day deliveryof a therapeutically effective amount of an active agent to a subjectwhen the composition is topically applied to said subject.

By multi-day delivery is meant that the layer is formulated to provide atherapeutically effective amount of the active agent to a subject whenthe composition is applied to a skin site of a subject for a period oftime that is 1 day or longer, such as 2 days or longer, e.g., 3 days orlonger, such as 5 days or longer, including 7 days or longer, such as 10days or longer. By therapeutically effective amount is meant that thecompositions, when applied to a skin site of a subject during itsintended time of application, e.g., within 7 days of application,provides for a systemic amount of active agent that provides a desiredtherapeutic activity. In some embodiments, the compositions providedelivery of a target dosage of active agent that is 0.5 mg/day orgreater over a one week period (i.e., 7 days or 168 hours), including1.0 mg/day or greater over a one week period, such as 10 mg/day orgreater over one week.

Transdermal compositions according to certain embodiments of theinvention exhibit a substantially constant flux of the active agent,e.g., propynylaminoindan, over an extended period of time. Bysubstantially constant flux is meant that the magnitude of any variationin flux over the extended period of time is 100% variation in flux orless, such as 80% variation in flux or less and including 50% variationin flux or less, e.g., 40% variation in flux or less, 30% variation influx or less, such as 25% variation in flux or less, such as 20%variation in flux or less, including 15% variation in flux or less,e.g., 10% variation in flux or less. The extended period of time overwhich substantially constant flux is observed may vary, and in someinstances is 24 hours or longer, such as 48 hours or longer, including72 hours or longer, e.g., 96 hours or longer. While the actual flux mayvary, in some instances (e.g., as determined using the skin permeationassay reported in the Experimental Section, below) skin permeation ratesof 0.5 μg/cm²/hr or greater, such as 1 μg/cm²/hr or greater, including10 μg/cm²/hr or greater are provided by the compositions. In someinstances, formulations of the invention exhibit substantially reducedburst delivery of agent immediately following application of theformulation to the skin, e.g., as compared to a control formulation inwhich the pressure sensitive adhesive does not include carboxylatedfunctionality (such as control pressure sensitive adhesives employed inthe Experimental Section, below). By substantially reduced burst deliveris meant a reduction of 10% or more, such as 20% or more, e.g., 25% ormore, 33% or more, 40% or more, 50% or more, including 66% or more, 75%or more, including 90% or more. In some instances, the formulations areconfigured to provide substantially zero-order delivery of the activeagent.

The size (i.e., area) of the transdermal compositions may vary. Incertain embodiments, the size of the composition is chosen in view ofthe desired transdermal flux rate of the active agent and the targetdosage. For example, if the transdermal flux is 3.4 μg/cm²/hr and thetarget dosage is 5 mg/day, then the transdermal composition is chosen tohave an area of about 43 cm². Or for example, if the transdermal flux is3.4 μg/cm²/hr and the target dosage is 10 mg/day, then the transdermalpatch is chosen have an area of about 87 cm². In certain embodiments,the compositions have dimensions chosen to cover an area of skin whenapplied to a skin site that ranges from 10 to 200, such as 20 to 150,including 40 to 140 cm².

The active agent and conversion layers of the compositions may vary inthickness. In some instances, the combined thickness of the layersranges from 25 to 250, such as 50 to 200, including 100 to 150micrometers. The various layers of the composition may have the samethicknesses or different thicknesses, as desired.

In some embodiments, the active agent and conversion layers areinsoluble in water. By insoluble in water is meant that that theselayers may be immersed in water for a period of 1 day or longer, such as1 week or longer, including 1 month or longer, and exhibit little if anydissolution, e.g., no observable dissolution.

An aspect of the transdermal compositions according to embodiments ofthe invention is that they are storage stable. By storage-stable ismeant that the compositions may be stored for extended periods of timewithout significant degradation and/or significant reduction in activityof the active agent. In certain embodiments, the subject compositionsare stable for 6 months or longer, such as 1 year or longer, including 2years or longer, e.g., 3 years or longer, etc., when maintained at 25°C. under sterile conditions. In some cases, the ratio of the amount ofactive in the composition to the initial amount of active agent in thecomposition after storage at about 60° C. for at least one month is 92%or more, 93% or more, such as 94% or more, including 95% or more, orgreater.

In some embodiments, the compositions of the invention include an activeagent layer 4, a converting layer 2, a backing layer 1 and release liner5, e.g., as shown in FIG. 1A. In some embodiments, the compositions ofthe invention include an active agent layer 4, a converting layer 2, asupport layer/rate controlling membrane 3 separating the active agentand converting layers, a backing layer 1 and release liner 5, e.g., asshown in FIG. 1B. Each of these layers is now described in greaterdetail.

Active Agent Layer

As reviewed above, transdermal compositions described herein include anactive agent layer. Active agent layers of interest include an amount ofan active agent present in a matrix. A variety of active agents may bepresent in the active agent layer. Of interest are active agents thatexhibit decreased storage stability in free base form. Such agents mayinclude agents that have a low melting temperature (Tm) in when in baseform, e.g., agents having a Tm of 120° C. or lower, such as 90° C. orlower. Agents of interest include agents that have a high vapor pressurewhen in base form, e.g., agents having a vapor pressure of 0.01 mmHg(25° C.) or higher, such as 0.05 mmHg or higher. A variety of differentactive agents may be present in the compositions, where such agentsinclude, but are not limited to: propynlaminoindans, e.g., rasagiline;rivastigmine; memantine; aminoesters, e.g., benzocaine, chloroprocaine,cyclomethycain, dimethocaine/larocaine, piperocaine, propoxycaine,procaine/novocaine, proparacaine, tetracaine/amethocaine; aminoamides,such as articaine, bupivacaine, cinchocaine/dibucaine, etidocaine,levobupivacaine, lidocaine/lignocaine, mepivacaine, prilocalne,ropivacaine, trimecaine, etc., and the like

In some instances, the active agent present in the active agent layer isa propynylaminoindan. Propynylaminoindans of interest include compoundsthat are described above the formula:

wherein R₁ is H, —OR₂, or

wherein R₂ is C₁-C₄ alkyl, and R₃ is H or C₁-C₄ alkyl. In someinstances, the propynylaminoindan is N-propargyl-1-aminoindan (i.e.,Rasagiline).

The active agent in the active agent layer, e.g., the propynylaminoindanactive agent, may be present in the matrix as a free base or salt, wherein certain instances the active agent is present as a salt.Pharmaceutically acceptable salts include, but are not limited to, themesylate, maleate, fumarate, tartrate, hydrochloride, hydrobromide,esylate, p-toluenesulfonate, benzoate, acetate, phosphate and sulfatesalts. In addition, the active agent, e.g., the propynylaminoindan, maybe present as a racemic mixture or as a pure enantiomer, such as the Ror L enantiomer of the active agent. For example, where the active agentis a propynylaminoindan, the propynylaminoindan in the matrix may solelyR(+)—N-propargyl-1-aminoindan free base, while in some instances, thepropylnylaminoindan may be solely R(+)—N-propargyl-1-aminoindanmesylate.

The amount of active agent, e.g., propynylaminoindan, present in theactive agent layer may vary. In some instances, the amount active agentmay range from 5 mg to 50 mg, such as 10 mg to 40 mg and including 15 mgto 30 mg. In some instances, the weight % of the active agent in theactive agent layer ranges from 5 to 25%, such as 10 to 20%.

As summarized above, the active agent layer includes an amount of activeagent (e.g., as described above) in a matrix. The matrix may vary asdesired, where the matrix may be adhesive or non-adhesive. Examples ofmatrix materials of interest include polymeric materials, wherepolymeric materials may vary widely and may include, but are not limitedto: polyurethanes; ethylene/vinyl acetate copolymers (EVA),polyacrylates, styrenic block copolymers, cellulosic polymers, and thelike. Suitable matrix materials may include, but are not limited to,polyacrylates, polysiloxanes, polyisobutylene (FIB), polyisoprene,polybutadiene, styrenic block polymers, blends and combinations of theabove, and the like. Suitable styrenic block copolymer-based adhesivesinclude, but are not limited to, styrene-isoprene-styrene blockcopolymer (SIS), styrene-butadiene-styrene copolymer (SBS),styrene-ethylenebutene-styrene copolymers (SEBS), and di-block analogsthereof. Suitable acrylic polymers are comprised of a copolymer orterpolymer comprising at least two or more exemplary components selectedfrom acrylic acids, alkyl acrylates, methacrylates, copolymerizablesecondary monomers or monomers with functional groups. Examples ofmonomers include, but are not limited to, acrylic acid, methacrylicacid, methoxyethyl acrylate, ethyl acrylate, butyl acrylate, butylmethacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate,2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate,2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decylmethacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate,tridecyl methacrylate, hydroxyethyl acrylate, hydroxypropyl acrylate,acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethylacrylate, dimethylaminoethyl methacrylate, tert-butylaminoethylacrylate, tert-butylaminoethyl methacrylate, methoxyethyl acrylate,methoxyethyl methacrylate, and the like.

Where desired (e.g., in configurations where the composition isconfigured such that, during use, the active agent layer contacts theskin), the active agent layer matrix may include a pressure sensitiveadhesive. The terms “pressure sensitive adhesive”, “self adhesive”, and“self stick adhesive” mean an adhesive that forms a bond when pressureis applied to adhere the adhesive with a surface. In some instances, theadhesive is one in which no solvent, water, or heat is needed toactivate the adhesive. For pressure sensitive adhesives, the degree ofbond strength is proportional to the amount of pressure that is used toapply the adhesive to the surface.

Pressure sensitive adhesives of the active agent layer of interestinclude, but are not limited to, acrylate copolymers. Acrylatecopolymers of interest include copolymers of various monomers which maybe “soft” monomers, “hard” monomers, and optionally “functional”monomers. Also of interest are blends including such copolymers. Theacrylate copolymers can be composed of a copolymer including bipolymer(i.e., made with two monomers), a terpolymer (i.e., made with threemonomers), or a tetrapolymer (i.e., made with four monomers), orcopolymers made from even greater numbers of monomers. The acrylatecopolymers can include cross-linked and non-cross-linked polymers. Thepolymers can be cross-linked by known methods to provide the desiredpolymers.

Monomers from which the acrylate copolymers are produced include atleast two or more exemplary components selected from the group includingacrylic acids, alkyl acrylates, methacrylates, copolymerizable secondarymonomers or monomers with functional groups. Monomers (“soft” and “hard”monomers) of interest include, but are not limited to, methoxyethylacrylate, ethyl acrylate, butyl acrylate, butyl methacrylate, hexylacrylate, hexyl methacrylate, 2-ethylbutyl acrylate, 2-ethylbutylmethacrylate, isooctyl acrylate, isooctyl methacrylate, 2-ethylhexylacrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate,dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, tridecylmethacrylate, acrylonitrile, methoxyethyl acrylate, methoxyethylmethacrylate, and the like. Additional examples of acrylic adhesivemonomers are described in Satas, “Acrylic Adhesives,” Handbook ofPressure-Sensitive Adhesive Technology, 2nd ed., pp. 396-456 (D. Satas,ed.), Van Nostrand Reinhold, New York (1989). Acrylic adhesives,available from several commercial sources, are sold under the tradenames AROSET, DUROTAK, EUDRAGIT, GELVA, and NEOCRYL.

In some instances, the active agent layer may include pressure sensitiveadhesive that includes a non-carboxylated polymer, e.g., Gelva 7883, anda carboxylated polymer. For the carboxylated polymer, of specificinterest are monomeric residues that provide for —COOH functionalgroups. Useful carboxylic acid monomers to provide the —COOH functionalgroup may contain from about 3 to about 6 carbon atoms and include,among others, acrylic acid, methacrylic acid, itaconic acid, and thelike. Acrylic acid, methacrylic acid and mixtures thereof are employedin certain embodiments. The functional monomer(s) are present in certainembodiments of the copolymers in an amount of 2 wt % or more, such asbetween 3-10 wt %.

In some embodiments, the active agent adhesive layer may include apressure sensitive adhesive which is a composition that is, or issubstantially the same as, a composition selected from the groupconsisting of: DuroTak® 87-2100 (Henkel), DuroTak® 87-2852 (Henkel), andthe like. The term “substantially the same” as used herein refers to acomposition that is an acrylate-vinyl acetate copolymer in an organicsolvent solution and provides for the functionality as described herein.In some embodiments, the acrylic pressure-sensitive adhesive is selectedfrom the group consisting of DuroTak® 87-2100, DuroTak® 87-2852, and thelike. The active agent layer may include a single pressure sensitiveadhesive, or a combination of two or more pressure sensitive adhesives.

In some instances, the pressure sensitive adhesive may make up from 50to 95, such as 60 to 90 and including 65 to 85% by weight of the matrix.

Conversion Layer

The conversion layer (i.e., converting layer, converting matrix oractive agent conversion layer) is a layer that serves to convert theactive agent salt in the active agent layer to free base form uponapplication of the composition to skin. The conversion layer ischaracterized, at least during storage and prior to skin contact or use,as having substantially less active agent (e.g., 5% by weight or less,such as 2.5% by weight or less, including 1% by weight or less) than theactive agent layer, where in some instances the conversion layerincludes substantially no active agent (e.g., 0.9% by weight or less,such as 0.5% or less, including no detectable active agent). Theconversion layer includes a converting agent, which may be any agentthat can mediate the conversion (either alone or in combination with oneor more other components) the active agent from salt form to free baseform. Converting agents of interest that may be present in theconverting layer include weak bases. By weak base is meant a base havinga base dissociation constant (K_(b)) of 10 or less, such as 9 or less.Any convenient weak base may be employed, such as polymeric weak bases,e.g., cationic acrylic copolymers, inorganic bases, e.g., calciumhydroxide; etc. Cationic acrylic copolymers of interest are polymers oftwo or more different monomeric residues, where at least one of theresidues is an acrylic residue, e.g., an acrylate or a methacrylate, andat least one of the residues includes a cationic pendant group, e.g., anamino pendant group, where these features may be included in the same ordifferent monomeric residues making up the copolymer. Where desired, thecationic acrylic copolymer may be an aminated methacrylate copolymer.The aminated methacrylate copolymer may be a copolymer ofdiethylaminoethyl methacrylate, butyl methacrylate and methylmethacrylate. Of interest are aminated methacrylate copolymers that aresubstantially the same as Eudragit® E100 aminated methacrylatecopolymer. As used herein, the term “substantially the same” means thatthe aminated methacrylate copolymer has the same functional impact onthe composition as Eudragit® E100 aminated methacrylate copolymer. Insome instances, the aminated methacrylate copolymer is Eudragit® E100aminated methacrylate copolymer. If present, the amount of cationicacrylic copolymer may be present in an amount ranging from 1 to 15, suchas 2 to 10 and including 4 to 8% by weight of the converting layer.

In addition to the converting agent, e.g., weak base, the conversionlayer further includes a matrix. In some instances, the matrix is apolymeric matrix, e.g., as described above in connection with the activeagent layer.

Where desired (e.g., in configurations where the composition isconfigured such that, during use, the conversion layer contacts theskin), the conversion layer includes a pressure sensitive adhesive,e.g., as described above. Pressure sensitive adhesives of interestinclude, but are not limited to carboxylated polymer, such ascarboxylated acrylate copolymers. Acrylate copolymers of interestinclude copolymers of various monomers which may be “soft” monomers,“hard” monomers, and optionally “functional” monomers. Also of interestare blends including such copolymers. The acrylate copolymers can becomposed of a copolymer including bipolymer (i.e., made with twomonomers), a terpolymer (i.e., made with three monomers), or atetrapolymer (i.e., made with four monomers), or copolymers made fromeven greater numbers of monomers. The acrylate copolymers can includecross-linked and non-cross-linked polymers. The polymers can becross-linked by known methods to provide the desired polymers. Monomersfrom which the acrylate copolymers are produced include at least two ormore exemplary components selected from the group including acrylicacids, alkyl acrylates, methacrylates, copolymerizable secondarymonomers or monomers with functional groups. Monomers (“soft” and “hard”monomers) of interest include, but are not limited to, methoxyethylacrylate, ethyl acrylate, butyl acrylate, butyl methacrylate, hexylacrylate, hexyl methacrylate, 2-ethylbutyl acrylate, 2-ethylbutylmethacrylate, isooctyl acrylate, isooctyl methacrylate, 2-ethylhexylacrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate,dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, tridecylmethacrylate, acrylonitrile, methoxyethyl acrylate, methoxyethylmethacrylate, and the like. Additional examples of acrylic adhesivemonomers are described in Satas, “Acrylic Adhesives,” Handbook ofPressure-Sensitive Adhesive Technology, 2nd ed., pp. 396-456 (D. Satas,ed.), Van Nostrand Reinhold, New York (1989).

Of interest are acrylate copolymers that include polar functionalmonomeric residues. Of specific interest are monomeric residues thatprovide for —COOH functional groups. Useful carboxylic acid monomers toprovide the —COOH functional group may contain from about 3 to about 6carbon atoms and include, among others, acrylic acid, methacrylic acid,itaconic acid, and the like. Acrylic acid, methacrylic acid and mixturesthereof are employed in certain embodiments. The functional monomer(s)are present in certain embodiments of the copolymers in an amount of 2wt % or more, such as between 3-10 wt %.

In some embodiments, the adhesive may have a composition that is, or issubstantially the same as, a composition selected from the groupconsisting of: DuroTak® 87-2100 (Henkel), DuroTak® 87-2852 (Henkel), andthe like. The term “substantially the same” as used herein refers to acomposition that is an acrylate-vinyl acetate copolymer in an organicsolvent solution and provides for the functionality as described herein.In some embodiments, the acrylic pressure-sensitive adhesive is selectedfrom the group consisting of DuroTak® 87-2100, DuroTak® 87-2852, and thelike. The converting layer may include a single pressure sensitiveadhesive, or a combination of two or more pressure sensitive adhesives.The pressure sensitive adhesive may be the same as or different fromthat present in the active agent layer.

In some instances, the pressure sensitive adhesive may make up from 50to 95, such as 60 to 90 and including 65 to 85% by weight of the matrix.

In addition to the weak base, the conversion layer may optionallyinclude a carboxylated component. By carboxylated component is meant acomponent of the layer, e.g., the matrix or an additional compound inthe matrix, that has a carboxyl moiety. As such, in some instances thecarboxylated component is a polymeric component, such as a matrixcomponent, e.g., a carboxylated polymer of a pressure sensitiveadhesive, such as described above. Additionally or alternatively, thecarboxylated component may be some other compound present in theconversion layer, such as small molecule, e.g., an organic acid, e.g.,ascrobic acid.

Permeation Enhancer

At least one of the active agent layer and the conversion layer, e.g.,as described herein, may contain a percutaneous absorption enhancer. Thepercutaneous absorption enhancer may facilitate the absorption of theactive agent by the skin of the subject. The percutaneous absorptionenhancer may also be referred to as a percutaneous permeation enhancerbecause it may facilitate not only the percutaneous absorption of theactive agent, but also the percutaneous permeation of the active agentthrough the skin of the subject. The percutaneous absorption enhancermay include, but is not limited to the following: aliphatic alcohols,such as but not limited to saturated or unsaturated higher alcoholshaving 12 to 22 carbon atoms, such as oleyl alcohol and lauryl alcohol;fatty acids, such as but not limited to linolic acid, oleic acid,linolenic acid, stearic acid, isostearic acid and palmitic acid; fattyacid esters, such as but not limited to isopropyl myristate, diisopropyladipate, and isopropyl palmitate; alcohol amines, such as but notlimited to triethanolamine, triethanolamine hydrochloride, anddiisopropanolamine; polyhydric alcohol alkyl ethers, such as but notlimited to alkyl ethers of polyhydric alcohols such as glycerol,ethylene glycol, propylene glycol, 1,3-butylene glycol, diglycerol,polyglycerol, diethylene glycol, polyethylene glycol, dipropyleneglycol, polypropylene glycol, sorbitan, sorbitol, isosorbide, methylglucoside, oligosaccharides, and reducing oligosaccharides, where thenumber of carbon atoms of the alkyl group moiety in the polyhydricalcohol alkyl ethers is preferably 6 to 20; polyoxyethylene alkylethers, such as but not limited to polyoxyethylene alkyl ethers in whichthe number of carbon atoms of the alkyl group moiety is 6 to 20, and thenumber of repeating units (e.g. —O—CH₂CH₂—) of the polyoxyethylene chainis 1 to 9, such as but not limited to polyoxyethylene lauryl ether,polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, andpolyoxyethylene oleyl ether; glycerides (i.e., fatty acid esters ofglycerol), such as but not limited to glycerol esters of fatty acidshaving 6 to 18 carbon atoms, where the glycerides may be monoglycerides(i.e., a glycerol molecule covalently bonded to one fatty acid chainthrough an ester linkage), diglycerides (i.e., a glycerol moleculecovalently bonded to two fatty acid chains through ester linkages),triglycerides (i.e., a glycerol molecule covalently bonded to threefatty acid chains through ester linkages), or combinations thereof,where the fatty acid components forming the glycerides include, but arenot limited to octanoic acid, decanoic acid, dodecanoic acid,tetradecanoic acid, hexadecanoic acid, octadecanoic acid (i.e., stearicacid) and oleic acid; middle-chain fatty acid esters of polyhydricalcohols; lactic acid alkyl esters; dibasic acid alkyl esters; acylatedamino acids; pyrrolidone; pyrrolidone derivatives; and combinationsthereof.

Additional types of percutaneous absorption enhancers include, but arenot limited to lactic acid, tartaric acid, 1,2,6-hexanetriol, benzylalcohol, lanoline, potassium hydroxide (KOH), andtris(hydroxymethyl)aminomethane.

Specific examples of percutaneous absorption enhancers include, but arenot limited to glycerol monooleate (GMO), sorbitan monolaurate (SML),sorbitan monooleate (SMO), laureth-4 (LTH), and combinations thereof.

In some cases, the matrix of at least one of the active agent layer andthe converting layer contains the percutaneous absorption enhancer in anamount ranging from 2% to 25% (w/w), such as from 5% to 20% (w/w), andincluding from 5% to 15% (w/w). In certain cases, the matrix containsthe percutaneous absorption enhancer in an amount of about 5% (w/w),about 10% (w/w), about 15% (w/w), or about 20% (w/w).

Where desired, antioxidants, such as BHA, BHT, propyl gallate,pyrogallol, tocopherol, etc. may also be incorporated into any one orall of the layers.

Structural Support/Rate-Controlling Membrane

In some embodiments, the transdermal formulations include anintermediate layer, e.g., non-woven PET, microporous polypropylene,etc., positioned between the active agent layer and the conversionlayer. In some embodiments, the intermediate layer may be arate-controlling membrane. The rate-controlling membrane meters thequantity of active agent that is administered through the skin for aprolonged period of time, such that the active agent is released fromthe transdermal formulation at a substantially constant rate until thedesired total quantity (i.e., target dosage) of active agent isadministered.

In certain embodiments, the rate-controlling membrane may be amicroporous membrane having pores that allow permeation of the activeagent. In these embodiments, the flux or release rate of the activeagent by the membrane is controlled by the rate of which the activeagent is able to diffuse through the pores of the membrane. Therate-controlling membrane may be any porous material that permits thepermeation of the active agent, such as but not limited topolypropylene, polyethylene, polyacrylonitrile, polytetrafluoroethylene,polydimethylsiloxane, polymethyl methacrylate, and combinations thereof.Additionally, the rate-controlling membrane may be single layer ormulti-layer (i.e., having one or more microporous membrane layerscomposed of the same or different material laminated together). Incertain embodiments, the rate-controlling membrane is a monolayerpolypropylene membrane.

The porosity, pore size and thickness of the rate-controlling membranedepend on the physicochemical properties, such as the molecular weightof the active agent, the flux required, and the like. For example, therate-controlling membrane may typically have the following properties: aporosity ranging from about 10% to 85%, including from about 20% to 75%,such as from 30% to 50%; a pore size ranging from 0.03-0.25 μm×μm,including 0.03-0.2 μm×μm, such as 0.04-0.12 μm×μm; and a thicknessranging from 10 μm to 70 μm, including from 15 μm to 60 μm, such as from20 μm to 50 μm. In certain embodiments, the rate-controlling membranemay have a porosity of 37%, a pore size of 0.04-0.12 μm×μm, and athickness of 25 μm.

In some embodiments, the rate-controlling membrane may have acomposition that is substantially the same as the composition ofCelgard® 2400 (Celgard LLC, Charlotte, N.C.). The term “substantiallythe same” as used herein refers to a composition that is a monolayerpolypropylene membrane and provides for the functionality as describedherein. In some embodiments, the rate-controlling membrane is Celgard®2400.

Multi-Layer Structure

As summarized above, the transdermal compositions described herein havea multi-layer structure. By multi-layer structure is meant that thecompositions include two or more distinct layers of differingcomposition, in addition to the backing (e.g., as described below),where the total number of distinct layers in the composition may be twoor more, such as 3 or more, including 4 or more, e.g., 5 or more. Insome instances, the number of distinct layers may range from 2 to 5,such as 2 to 4, including 2 to 3. For example, one may have aconfiguration in which a converting layer is present between first andsecond conversion layers. As mentioned above, the thicknesses of each ofthe layers in the composition may be the same or different, as desired.

Backing

As summarized above, transdermal compositions of interest may include abacking (i.e., support layer). The backing may be flexible to an extentthat it can be brought into close contact with a desired topicallocation of a subject. The backing may be fabricated from a materialthat it does not absorb the active agent, and does not allow the activeagent to be released from the side of the support. The backing mayinclude, but is not limited to, non-woven fabrics, woven fabrics, films(including sheets), porous bodies, foamed bodies, paper, compositematerials obtained by laminating a film on a non-woven fabric or fabric,and combinations thereof.

Non-woven fabric may include, but is not limited to, the following:polyolefin resins such as polyethylene and polypropylene; polyesterresins such as polyethylene terephthalate, polybutylene terephthalateand polyethylene naphthalate; rayon, polyamide, poly(ester ether),polyurethane, polyacrylic resins, polyvinyl alcohol,styrene-isoprene-styrene copolymers, andstyrene-ethylene-propylene-styrene copolymers; and combinations thereof.Fabrics may include, but are not limited to: cotton, rayon, polyacrylicresins, polyester resins, polyvinyl alcohol, and combinations thereof.Films may include, but are not limited to the following: polyolefinresins such as polyethylene and polypropylene; polyacrylic resins suchas polymethyl methacrylate and polyethyl methacrylate; polyester resinssuch as polyethylene terephthalate, polybutylene terephthalate andpolyethylene naphthalate; and besides cellophane, polyvinyl alcohol,ethylene-vinyl alcohol copolymers, polyvinyl chloride, polystyrene,polyurethane, polyacrylonitrile, fluororesins, styrene-isoprene-styrenecopolymers, styrene-butadiene rubber, polybutadiene, ethylene-vinylacetate copolymers, polyamide, and polysulfone; and combinationsthereof. Papers may include, but are not limited to, impregnated paper,coated paper, wood free paper, Kraft paper, Japanese paper, glassinepaper, synthetic paper, and combinations thereof. Composite materialsmay include, but are not limited to, composite materials obtained bylaminating the above-described film on the above-described non-wovenfabric or fabric.

The size of the backing may vary, and in some instances the backing issized to cover the desired topical target site. In some embodiments, thebacking has a length ranging from 2 to 100 cm, such as 4 to 60 cm and awidth ranging from 2 to 100 cm, such as 4 to 60 cm.

In some embodiments, the backing layer is insoluble in water. Byinsoluble in water is meant that that the backing layer may be immersedin water for a period of 1 day or longer, such as 1 week or longer,including 1 month or longer, and exhibit little if any dissolution,e.g., no observable dissolution.

The backing layer may be in contact with a surface of the convertinglayer or the active agent layer, as desired, e.g., depending on whetherthe composition is configured so that the converting layer or the activeagent layer contacts the skin upon application to a subject. Forexample, where the composition is configured so that the active agentlayer contacts the skin upon application, the backing will be in contactwith a surface of the active agent layer. Alternatively, where thecomposition is configured so that the converting layer contacts the skinupon application, the backing will be in contact with a surface of theconverting layer.

Release Liner

In some embodiments, a release liner is provided on the active agentlayer (i.e., matrix), and specifically on a surface of the active agentlayer that is distal (i.e. opposite) from the backing layer, if present.The release liner facilitates the protection of the active agent layer.The release liner may be prepared by treating one side ofpolyethylene-coated wood free paper, polyolefin-coated glassine paper, apolyethylene terephthalate (polyester) film, a polypropylene film, orthe like with a silicone treatment. The release liner may be in contactwith a surface of the converting layer or the active agent layer, asdesired, e.g., depending on whether the composition is configured sothat the converting layer or the active agent layer contacts the skinupon application to a subject. For example, where the composition isconfigured so that the active agent layer contacts the skin uponapplication, the release liner will be in contact with a surface of theactive agent layer. Alternatively, where the composition is configuredso that the converting layer contacts the skin upon application, therelease liner will be in contact with a surface of the converting layer.

Methods of Use

Methods of using the product transdermal compositions includeadministering an effective amount of the active agent to a subject inorder to treat the subject for a target condition of interest, e.g., asdescribed in the Utility section below. By “treating” or “treatment” ismeant at least a suppression or an amelioration of the symptomsassociated with the condition afflicting the subject, where suppressionand amelioration are used in a broad sense to refer to at least areduction in the magnitude of a parameter, e.g., symptom, associatedwith the condition being treated. As such, treatment also includessituations where the condition is completely inhibited, e.g., preventedfrom happening, or stopped, e.g., terminated, such that the subject nolonger experiences the condition. As such, treatment includes bothpreventing and managing a condition.

In practicing the methods, the transdermal compositions disclosed hereincan be topically administered to a subject, i.e., the transdermalcompositions may be administered to any convenient topical site (e.g.,skin site). Application may include contacting an active agent layer ora converting layer to a skin site of the subject, depending on theconfiguration of the transdermal composition. Topical sites of interestinclude both mucosal sites and keratinized skin sites, and thereforeinclude, but are not limited to: mouth, nose, eyes, rectum, vagina,arms, leg, torso, head, etc. The surface area that is covered by thetopical composition following application is sufficient to provide forthe desired amount of agent administration, and in some embodimentsranges from 1 to 200 cm², such as from 10 to 180 cm², and including from100 to 150 cm², e.g., 140 cm².

The transdermal composition may be maintained at the topical site towhich it has been applied for a desired amount of time, e.g., to delivera desired amount of active agent delivery. In some instances, the periodof time that the composition is maintained at the site of application is24 hours or longer, such as 48 hours or longer, e.g., 72 hours orlonger, such as 96 hours or longer.

In practicing the subject methods, a given dosage of the transdermalcomposition may be applied a single time or a plurality of times over agiven time period, e.g., the course of the disease condition beingtreated, where the dosing schedule when a plurality of compositions areadministered over a given time period may be daily, weekly, biweekly,monthly, etc.

The area of skin covered by the topical composition when applied mayvary. In some instances, the area of skin covered by the topicalcomposition upon application ranges from 1 to 200 cm², such as 10 to 180cm² and including 100 to 150 cm².

After the transdermal active agent composition has been applied to theskin site for the desired amount of time (i.e., an amount of timesufficient to deliver a target dose of the active agent to the subjectover a period of time), the composition may be removed from the skinsite. A new transdermal composition may be applied at the same or at adifferent skin site. The new transdermal composition may be applied to adifferent skin site to reduce the possible occurrence of skin irritationand/or skin sensitization at the prior site of application.

In certain embodiments, the subject methods include a diagnostic step.Individuals may be diagnosed as being in need of the subject methodsusing any convenient protocol. In addition, individuals may be known tobe in need of the subject methods, e.g., they are suffering fromParkinson's disease. Diagnosis or assessment of target condition can beperformed using any convenient diagnostic protocol.

Methods of the invention may further include assessing the efficacy ofthe treatment protocol that includes administration of the localanesthetic emulsion composition. Assessing the efficacy of treatment maybe performed using any convenient protocol.

In some instances, transdermal compositions may be administering inconjunction with one or more additional therapies specific for thetarget condition of interest. As such, the transdermal compositions maybe used alone to treat the target disorder, or alternatively, as in thecase of Parkinson's disease, for example, they may be used as an adjunctto the conventional L-DOPA treatments.

Transdermal compositions of the invention may be administered to avariety of different types of subjects. Subjects of interest include,but are not limited to: mammals, both human and non-human, including theorders carnivore (e.g., dogs and cats), rodentia (e.g., mice, guineapigs, and rats), lagomorpha (e.g. rabbits) and primates (e.g., humans,chimpanzees, and monkeys). In certain embodiments, the subjects, e.g.,patients, are humans.

Utility

The transdermal compositions of the invention find use in anyapplication where a subject would benefit from being transdermallyadministered an active agent, such as a propynylaminoindan, e.g.,rasagiline. Rasagiline and/or its salts find use in the treatment of avariety of different disease conditions, such as but not limited to:Parkinson's disease, Alzheimer's Disease, memory disorders, stroke andother disorders, e.g., as described in U.S. Pat. Nos. 5,387,612;5,453,446; 5,457,133; 5,668,181; 5,576,353; 5,532,415; 5,599,991;5,786,390; 5,519,061; 5,891,923; 5,744,500 and 6,316,504, the contentsof which are hereby incorporated by reference. By treatment is meantthat at least an amelioration of the symptoms associated with thecondition afflicting the subject is achieved, where amelioration is usedin a broad sense to refer to at least a reduction in the magnitude of aparameter, e.g., symptom, associated with the condition being treated.As such, treatment also includes situations where the pathologicalcondition, or at least symptoms associated therewith, are completelyinhibited, e.g., prevented from happening, or stopped, e.g., terminated,such that the subject no longer suffers from the condition, or at leastthe symptoms that characterize the condition.

Kits

Kits for use in practicing certain methods described herein are alsoprovided. In certain embodiments, the kits include one or moretransdermal compositions as described above. In certain embodiments, thekits include an adhesive overlay as described above. In someembodiments, the kits include multilayers such as a layer containingdrug and a layer that may or may not contain any drug and otherexcipients. In a given kit that includes two or more compositions, thecompositions may be individually packaged or present within a commoncontainer.

In certain embodiments, the kits will further include instructions forpracticing the subject methods or means for obtaining the same (e.g., awebsite URL directing the user to a webpage which provides theinstructions), where these instructions may be printed on a substrate,where substrate may be one or more of: a package insert, the packaging,reagent containers and the like. In the subject kits, the one or morecomponents are present in the same or different containers, as may beconvenient or desirable.

The following examples are offered by way of illustration and not by wayof limitation. Specifically, the following examples are of specificembodiments for carrying out the present invention. The examples are forillustrative purposes only, and are not intended to limit the scope ofthe present invention in any way.

EXAMPLES I. Introduction

In certain embodiments, the active agent is a propynylaminoindan, suchas rasagiline. Embodiments of the present invention overcomedisadvantages of other transdermal rasagiline formulations. Rasagilinehas to penetrate across skin in free base form in order to delivertherapeutic effective dose for a sustained period of time, such as up to7 days. Rasagiline free base is not stable at room temperature and candegrade quickly during room temperature storage. Therefore, the use ofrasagiline free base in a formulation is not a feasible option. Toaddress degradation issue, rasagiline in salt form, such as rasagilinemesylate, is employed in formulations of the invention since rasagilinesalt typically has higher melting point and is more stable. Since drugin a salt form has very low penetration rate across skin, patches of theinvention include a weak base, such as Eudragit or dimethyl triamine, inthe formulation to facilitate the conversion of rasagiline salt to base.To further balance the conversion from salt to base to avoid burstdelivery, embodiments of the invention may additionally utilize acarboxylated component, such as a pressure sensitive adhesive thatcontains a carboxylated functionality or a low molecular weightcomponent that includes a carboxylated functionality, e.g., an organicacid. In these embodiments, the interaction between the weak base,active carboxylated component provides for an optimized delivery of thedrug, such as rasagiline, across skin.

In formulations according to aspects of the invention, stability of theformulation during storage is improved by configuring the formulation sothat conversion of drug to free base upon combination with the weak baseis minimized, if not substantially eliminated during storage period. Toprovide this storage stability, embodiments of the invention employ mayemploy a multi-layer, e.g., a two-layer, system design. In thisconfiguration, drug is present in one layer (i.e., the active agentlayer) and the material that can be used to convert drug from salt formto free base form is provided in a second layer (i.e., the active agentconversion layer). The selection of matrix material and weak base issuch that there will is no migration happening during storage period. Assoon as the patch is placed on skin, the resultant normal transpirationstream of moisture activates conversion of the salt form of the activeagent to free base. To ensure this in certain embodiments of theinvention, drug in salt form is used to disperse in a matrix that haslow solubility for the drug. Weak base also having low mobility isemployed. The novel multilayer, e.g., two-layer, configuration of thetransdermal composition can be used not only for rasagiline, but alsoany drugs that might have the similar stability problems in their freebase form.

II. Preparation of Drug Layer and Converting Layer

Formulations were prepared by mixing drug, excipients, and stocksolutions adhesives in organic solvents (typically 30-60 wt % solidcontent in ethyl acetate, and/or methanol, ethanol, toluene), followedby a mixing process. Once a homogeneous mixture was formed, the solutionwas cast on a release liner (siliconized polyester sheet of 2-3 mils)and dried at 65°-80° C. for 10-90 minutes. The adhesive films werelaminated to a PET backing. The final formulations were prepared bylaminating drug layer and converting layer together before the fluxexperiment.

III. Transdermal Flux Tests

Human cadaver skin was used and epidermal layers (stratum corneum andepidermis) were separated from the full-thickness skin as skin membrane.Samples were die-cut with an arch punch to a final diameter of about 2.0cm². The release liner was removed and the system was placed on top ofthe epidermis/stratum corneum with the drug adhesive layer facing thestratum corneum. Gentle pressure was applied to effect good contactbetween the adhesive layer and stratum corneum. The donor and receptorsides of the Franz cell were clamped together and the receptor solutioncontaining a phosphate buffer at pH 6.5 was added to the Franz cell. Thecells were kept at 33° C. for the duration of the experiment. Samples ofthe receptor solution were taken at regular intervals and the activeagent concentration was measured by HPLC. The removed receptor solutionwas replaced with fresh solution to maintain the sink conditions. Theflux was calculated from the slope of cumulative amounts of the drug inthe receiver compartment versus time plot.

IV. Specific Examples A. Flux of Rasagiline Mesylate in AcrylateAdhesive: Two Layer Design

Using the general method described previously, a series of transdermalsystems were prepared with details shown in following table. The fluxthrough human cadaver skin was measured and the results are graphicallypresented in FIG. 2. Compared to one layer design, two layer design haslower flux at the beginning and shows a more flat delivery profile. Thedata also shows that without using converting agent E100, the flux ismuch lower.

TABLE 1 Sample Drug layer Converting layer Application/design 1 10%rasagiline None One layer design mesylate, 3% E100¹ with Scotchpak in inDuro-Tak 9723 as backing 2100 and Gelva 7883² (adhesive ratio 1:3) 2 20%rasagiline 6% E100 in Duro- Two layer design mesylate in Tak 2100 andGelva with Scotchpak Gelva 7883 7883 (adhesive ratio 9723 as backing,1:3) drug layer in contact with skin 3 20% rasagiline 0% E100 in Duro-Same as #2 except mesylate in Tak 2100 and Gelva no E100 in Gelva 78837883 (adhesive ratio converting layer 1:3) Notes. 1. Both Duro-Tak 2100(Henkel) and Gelva 7883 (Cytec) are acrylate based pressure sensitiveadhesives. 2. E100 is Eudragit E100 (Evonik)

B. Flux of Rasagiline Mesylate in Acrylate Adhesive: Effect of SystemDesign

Using the general method described previously, a series of transdermalsystems were prepared with details shown in following table. The fluxthrough human cadaver skin was measured and the results are graphicallypresented in FIG. 3. In this particular experiment, comparison was madebetween sample with drug layer in contact with skin and converting layerin contact with skin. Higher flux was seen when drug layer is the skincontacting layer.

TABLE 2 Sample Drug layer Converting layer Application/design 1 20%rasagiline 6% E100 in Two layer design mesylate in Duro-Tak 2100 withScotchpak Gelva 7883 and Gelva 7883¹ 9723 as backing, (adhesive druglayer in ratio 1:3) contact with skin 4 20% rasagiline 6% E100² in Twolayer design mesylate in Duro-Tak 2100 with Scotchpak Gelva 7883 andGelva 7883 9723 as backing, (adhesive converting layer in ratio 1:3)contact with skin Notes. 1. Both Duro-Tak 2100 (Henkel) and Gelva 7883(Cytec) are acrylate based pressure sensitive adhesives. 2. E100 isEudragit E100 (Evonik)

C. Flux of Rasagiline Mesylate in Acrylate Adhesive: Effect of Adhesive

Using the general method described previously, a series of transdermalsystems were prepared with details shown in following table. The fluxthrough human cadaver skin was measured and the results are graphicallypresented in FIG. 4. In this particular experiment, comparison was madebetween samples with different drug loadings and different adhesiveratios.

TABLE 3 Sample Drug layer Converting layer Application/design 1 20%rasagiline 6% E100 in Two layer design mesylate in Duro-Tak 2100 withScotchpak Gelva 7883 and Gelva 9723 as backing, 7883 (adhesive druglayer in ratio 1:3) contact with skin 5 20% rasagiline 3% E100 in Twolayer design mesylate in Duro-Tak 2100 with Scotchpak Gelva 7883 andGelva 9723 as backing, 7883 (adhesive drug layer in ratio 1:3) contactwith skin 6 20% rasagiline 6% E100 in Two layer design mesylate inDuro-Tak 2100 with Scotchpak Duro-Tak 2100 and Gelva 9723 as backing,and Gelva 7883 7883 (adhesive drug layer in (adhesive ratio 1:3) ratio5:17) contact with skin 7 20% rasagiline 6% E100² in Two layer designmesylate in Duro-Tak 2100 with Scotchpak Duro-Tak 2100 and Gelva 9723 asbacking, and Gelva 7883¹ 7883 (adhesive drug layer in (adhesive ratio1:3) ratio 1:3) contact with skin 8 10% rasagiline 3% E100 in Duro- Twolayer design mesylate in Tak 2100 and Gelva with Scotchpak Duro-Tak 21007883 (adhesive 9723 as backing, and Gelva 7883 ratio 1:3) drug layer in(adhesive ratio 1:3) contact with skin Notes. 1. Both Duro-Tak 2100(Henkel) and Gelva 7883 (Cytec) are acrylate based pressure sensitiveadhesives. 2. E100 is Eudragit E100 (Evonik)

D. Flux of Rasagiline Mesylate in Acrylate Adhesive: Effect of Loading

Using the general method described previously, a series of transdermalsystems were prepared with details shown in following table. The fluxthrough human cadaver skin was measured and the results are graphicallypresented in FIG. 5. In this particular experiment, comparison was madebetween samples with and without a membrane that can serve as bothstructural support and/or rate control.

TABLE 4 Sample Drug layer Converting layer Application/design  9 10%rasagiline 6% E100² in Two layer design mesylate in Duro-Tak 2100 withScotchpak Duro-Tak 2100 and Gelva 9723 as backing, and Gelva 7883¹ 7883(adhesive drug layer in (adhesive ratio 1:3) ratio 1:3) contact withskin 10 10% rasagiline 6% E100 in Same as #9 except mesylate in Duro-Tak2100 that there is a Duro-Tak 2100 and Gelva Celgard 2400 and Gelva 78837883 (adhesive membrane (adhesive ratio 1:3) ratio 1:3) between twolayer 11 10% rasagiline 6% E100 in Two layer design mesylate in Duro-Tak2100 with Scotchpak Gelva 7883 and Gelva 9723 as backing, 7883 (adhesivedrug layer in ratio 1:3) contact with skin 12 10% rasagiline 6% E100 inSame as #9 except mesylate in Duro-Tak 2100 that there is a Gelva 7883and Gelva Celgard 2400³ 7883 (adhesive membrane ratio 1:3) between twolayer Notes. 1. Both Duro-Tak 2100 (Henkel) and Gelva 7883 (Cytec) areacrylate based pressure sensitive adhesives. 2. E100 is Eudragit E100(Evonik) 3. Celgard 2400 is from Celgard and serves as structuralsupport and rate control.

E. Flux of Rasagiline Mesylate in Acrylate Adhesive: Effect of Loading

Using the general method described previously, a series of transdermalsystems were prepared with details shown in following table. The fluxthrough human cadaver skin was measured and the results are graphicallypresented in FIG. 6. In this particular experiment, comparison was madebetween samples with and without the use of converting agent E100.

TABLE 5 Sample Drug layer Converting layer Application/design 13 10%rasagiline 10% E100² in Two layer design mesylate in Duro-Tak 2100 withScotchpak Duro-Tak 2100 and Gelva 7883 9723 as backing, and Gelva 7883¹(adhesive drug layer in (adhesive ratio 1:3) ratio 1:3) contact withskin 14 10% rasagiline 6% E100 in Two layer design mesylate in Duro-Tak2100 with Scotchpak Gelva 7883 and Gelva 7883 9723 as backing, (adhesivedrug layer in ratio 1:3) contact with skin 15 10% rasagiline None Onelayer design mesylate in with Scotchpak Gelva 7883 9723 as backing andno E100 Notes. 1. Both Duro-Tak 2100 (Henkel) and Gelva 7883 (Cytec) areacrylate based pressure sensitive adhesives. 2. E100 is Eudragit E100(Evonik)

IV. Stability Testing

A two layer patch summarized below was prepared using the protocoldescribed above.

TABLE 6 Sample Drug layer Converting layer Application/design 16 10%rasagiline 10% E100² in Two layer design mesylate in Duro-Tak 2052 withScotchpak Gelva 7883², and Gelva 9723 as backing, 0.5% BHT³ 7883(adhesive drug layer in ratio 3:97) contact with skin Notes. 1. E100 isEudragit E100 (Evonik) 2. Duro-Tak 2100, Duro-Tak 2052, Duro-Tak 900a,Duro-Tak 9301 (Henkel), Gelva 7883, and Gelva 2999 (Cytec) are acrylatebased pressure sensitive adhesives. 3. BHT is anti-oxidant Butylatedhydroxytoluene

The test patches were prepared at 4 cm² size, pouched and sealed using

Polyacrylonitrile (PAN) material. The patches were stored at in roomtemperature, 30° C. and 40° C. chambers. At selected time points, thepatches were extracted to determine Rasagiline Mesylate and 1-Aminoindan(main degradent) concentration. The stability of the patches wasdetermined by high performance liquid chromatography (HPLC). The resultsare provided in Table 7, below:

Con- T = 0 1 month 2 months 3 months dition API 1-AI API 1-AI API 1-AIAPI 1-AI RT 100 0.01 98.4 0.00 99.7 0.13 102.0 0.02 (±0.4) (±1.6) (±2.4)(±2.5) 30° — — 96.0 0.00 98.0 0.13 98.2 0.12 C. (±6.1) (±5.8) (±5.8) 40°— — 96.3 0.05 95.1 0.47 99.2 0.37 C. (±7.1) (±6.7) (±3.9)

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

Accordingly, the preceding merely illustrates the principles of theinvention. It will be appreciated that those skilled in the art will beable to devise various arrangements which, although not explicitlydescribed or shown herein, embody the principles of the invention andare included within its spirit and scope. Furthermore, all examples andconditional language recited herein are principally intended to aid thereader in understanding the principles of the invention and the conceptscontributed by the inventors to furthering the art, and are to beconstrued as being without limitation to such specifically recitedexamples and conditions. Moreover, all statements herein recitingprinciples, aspects, and embodiments of the invention as well asspecific examples thereof, are intended to encompass both structural andfunctional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalentsdeveloped in the future, i.e., any elements developed that perform thesame function, regardless of structure. The scope of the presentinvention, therefore, is not intended to be limited to the exemplaryembodiments shown and described herein. Rather, the scope and spirit ofpresent invention is embodied by the appended claims.

What is claimed is:
 1. A transdermal composition comprising: an activeagent layer comprising an active agent in a matrix; and a conversionlayer comprising a weak base in a matrix.
 2. The transdermal compositionaccording to claim 1, wherein the conversion layer comprises acarboxylated component.
 3. The transdermal composition according toclaim 1, wherein the active agent is present as a salt.
 4. Thetransdermal composition according to claim 3, wherein the active agentis a propynylaminoindan.
 5. The transdermal composition according toclaim 4, wherein the propynylaminoindan is N-propargyl-1-aminoindan. 6.The transdermal composition according to claim 1, wherein thecarboxylated component of the conversion layer is an acryliccarboxylated polymer.
 7. The transdermal composition according to claim6, wherein the acrylic carboxylate polymer is the acrylic carboxylatepolymer present in DuroTak® 87-2100 pressure-sensitive adhesive.
 8. Thetransdermal composition according to claim 1, wherein the carboxylatedcomponent of the conversion layer is a low molecular weight organicacid.
 9. The transdermal composition according to claim 8, wherein thelow molecular weight organic acid is acetic acid.
 10. The transdermalcomposition according to claim 1, wherein the weak base of theconversion layer is a cationic acrylic copolymer.
 11. The transdermalcomposition according to claim 10, wherein the cationic acryliccopolymer is an aminated methacrylate copolymer.
 12. The transdermalcomposition according to claim 11, wherein the aminated methacrylatecopolymer is a copolymer of diethylaminoethyl methacrylate, butylmethacrylate and methyl methacrylate.
 13. The transdermal compositionaccording to claim 12, wherein the aminated methacrylate copolymer isEudragit® E100 aminated methacrylate copolymer.
 14. The transdermalcomposition according to claim 1, wherein the matrix of the active agentlayer comprises a carboxylated polymer.
 15. The transdermal compositionaccording to claim 1, wherein the transdermal composition comprises apressure sensitive adhesive.
 16. The transdermal composition accordingto claim 1, wherein the transdermal composition comprises a permeationenhancer.
 17. The transdermal composition according to claim 1, whereinthe transdermal composition comprises a rate-controlling layer betweenthe active agent layer and the active agent conversion layer.
 18. Thetransdermal composition according to claim 1, wherein the compositioncomprises at least one additional layer.
 19. The transdermal compositionaccording to claim 1, wherein the transdermal composition exhibits aconstant flux of the active agent over an extended period of time.
 20. Amethod comprising: applying to a skin surface of a subject a transdermalcomposition comprising: an active agent layer comprising an active agentin a matrix; and a conversion layer comprising a weak base in a matrix;in a manner sufficient to achieve a constant flux of the active agentover an extended period of time.
 21. The method according to claim 20,wherein the extended period of time is 72 hours or longer.
 22. Themethod according to claim 20, wherein the conversion layer comprises acarboxylated component.
 23. The method according to claim 20, whereinthe active agent is a propynylaminoindan.
 24. The method according toclaim 23, wherein the propynylaminoindan is N-propargyl-1-aminoindan.25. A kit comprising: two or more transdermal compositions, wherein eachtransdermal composition comprises: an active agent layer comprising anactive agent in a matrix; and a conversion layer comprising a weak basein a matrix.
 26. The kit according to claim 25, wherein the conversionlayer comprises a carboxylated component.